Neuroprotective Properties of a Novel Glaucoma Drug and Formulation

青光眼是世界上导致不可逆转失明的主要原因，目前影响着世界上300多万人 预计到2050年将增加到~630万。四种主要类型的成人型青光眼都是 通过视网膜神经节细胞(RGC)功能障碍和/或死亡的最终共同途径导致视力丧失。这个 目前的护理标准包括使用降眼压眼药水治疗，所有这些治疗效果都有限。 具体地说，降低眼压并不能完全防止许多青光眼的RGC死亡和由此导致的视野丧失 病人。在我们之前由美国国立卫生研究院资助的研究中，我们确定了一种新的降低眼压的药物靶点，即钙 通道，电压依赖，α2δ1亚单位(又名CACNA2D1)和选择性CACNA2D1阻滞剂， 普瑞巴林(PRG)，可降低眼压。最后，我们开发了局部缓释PRG微乳(ME)。 这会增加药物进入眼睛的可能性，从而导致更高的疗效和持续时间。我们最新的 研究发现了PRG一个意想不到的额外治疗益处，即它的额外本地化。 对视网膜节细胞和视神经的作用和神经保护，正如我们在正常动物模型中所展示的那样。 紧张性青光眼。因此，PRG ME可能是第一个既能降低眼压又能直接、 视网膜节细胞及其轴突的神经保护作用。当前的SBIR第一阶段应用旨在 验证我们关于PRG ME神经保护作用的新发现，并建立其机制 行动的一部分。我们的中心假设是，我们的PRG ME将以更好的疗效降低眼压，并保持 RGCs的健康，这是一个目前没有FDA批准的药物的使用领域。这一假设是 我们的数据显示CACNA2D1位于视网膜节细胞和视网膜节细胞内，局部给药 我们的缓释生物粘附剂ME可促进PRG向视网膜的输送。本项目的整体优势 包括：1)一支强大和经验丰富的跨学科眼科治疗团队；2)设计一种创新的 使用缓释制剂的给药策略；3)使用前景看好的FDA批准的药物 这将被重新用于治疗青光眼；以及4)发现该药物可能有多个部位 通过与睫状体的直接相互作用共同提供眼压降低的眼内活动 和/或流出结构以及独立于其降低眼压的直接RGC神经保护 能力。在此第一阶段SBIR提案中，我们将提供概念证明并解决关键的可行性问题 通过建立我们的PRG ME的神经保护作用和作用机制。这一治疗策略将 减轻患者负担，为青光眼患者带来更好的视力结果。向我们的 目的，我们提出以下目标：目标1：我们验证了PRG是一种神经保护剂的假设 RGCs和On每日给药一次。目的2：我们验证了PRG在RGC中起直接作用的假设 通过调节细胞内钙离子浓度(Ca~(2+))对人体健康产生影响。

Glaucoma, the leading cause of irreversible blindness in the world; currently affects more than 3 million in the U.S. and is projected to increase to ~6.3 million by 2050. The four major types of adult-onset glaucoma all lead to vision loss through a final common pathway of retinal ganglion cell (RGC) dysfunction and/or death. The current standard of care includes treatment with IOP-lowering eye drops, all of which have limited efficacy. Specifically, IOP reduction does not fully prevent RGC death and resulting visual field loss in many glaucoma patients. In our previous NIH-funded studies, we identified both a novel IOP-lowering drug target, the calcium channel, voltage-dependent, α2δ1subunit (aka CACNA2D1) and a selective CACNA2D1 blocker, pregabalin (PRG), that lowers IOP. Lastly, we developed a topical extended release PRG microemulsion (ME) that increases drug entry into the eye, resulting in higher efficacy and duration of action. Our most recent studies have uncovered an unanticipated additional treatment benefit of PRG, namely its additional localization to, and neuroprotection of, RGCs and optic nerve (ON) as we have demonstrated in an animal model of normal tension glaucoma. Thus, PRG ME could be the first glaucoma therapy to both lower IOP and have direct, neuroprotective effects on RGCs and their axons. This current SBIR Phase I application is designed to validate our new findings regarding the neuroprotective effects of our PRG ME, and to establish its mechanism of action. Our central hypothesis is that our PRG ME will lower IOP with improved efficacy, as well as maintain the health of RGCs, a field of use for which there is currently no FDA-approved drug. This hypothesis is supported by our data showing that CACNA2D1 is located in RGCs and ON and that topical administration of our extended-release bioadhesive ME promotes delivery of PRG to the retina. Overall strengths of this project include: 1) a strong and experienced interdisciplinary OculoTherapy team; 2) engineering of an innovative delivery strategy using an extended-release formulation; 3) the use of a highly promising FDA-approved drug that will be repurposed as a glaucoma therapeutic; and 4) the discovery that the drug may have multiple sites of action within the eye that collectively provide IOP lowering through direct interactions with the ciliary body and/or outflow structures as well as direct RGC neuroprotection that is independent of its IOP-lowering capability. In this Phase I SBIR proposal, we will provide proof of concept and address key feasibility questions by establishing neuroprotective efficacy and mechanism of action of our PRG ME. This treatment strategy will reduce the burden to the patient and lead to better visual outcomes for glaucoma patients. To address our objective, we propose the following Aims: Aim 1: We test the hypothesis that PRG is a neuroprotectant for RGCs and the ON using once daily dosing. Aim 2: We test the hypothesis that PRG plays a direct role in RGC health by regulating the concentration of intracellular calcium (Ca2+).